Ouach Aziz, Pin Frederic, Bertrand Emilie, Vercouillie Johnny, Gulhan Zuhal, Mothes Céline, Deloye Jean-Bernard, Guilloteau Denis, Suzenet Franck, Chalon Sylvie, Routier Sylvain
Universite Orleans, CNRS, ICOA, UMR 7311, F-45067 Orleans, France.
UMR Inserm U930, Universite François Rabelais de Tours, CHRU de Tours, Tours, France.
Eur J Med Chem. 2016 Jan 1;107:153-64. doi: 10.1016/j.ejmech.2015.11.001. Epub 2015 Nov 10.
We report here the synthesis of a large library of 1,2,3-triazole derivatives which were in vitro tested as α7 nAchR ligands. The SAR study revealed that several crucial factors are involved in the affinity of these compounds for α7 nAchR such as a (R) quinuclidine configuration and a mono C-3 quinuclidine substitution. The triazole ring was substituted by a phenyl ring bearing small OMe/CH2F groups or fluorine atom and by several heterocycles such as thiophenes, furanes, benzothiophenes or benzofuranes. Among the 30 derivatives tested, the two derivatives 10 and 39 with Ki in the nanomolar range were identified (2.3 and 3 nM respectively). They exhibited a strict selectivity toward the α4β2 nicotinic receptor (up to 1 μM) but interacted with the 5HT3 receptors with Ki around 3 nM. Synthesis, SAR studies and a full description of the derivatives are reported.
我们在此报告了一个大型1,2,3 - 三唑衍生物库的合成，这些衍生物作为α7烟碱型乙酰胆碱受体（α7 nAchR）配体进行了体外测试。构效关系（SAR）研究表明，这些化合物对α7 nAchR的亲和力涉及几个关键因素，如（R）奎宁环构型和单C - 3奎宁环取代。三唑环被带有小的甲氧基/二氟甲基基团或氟原子的苯环以及几种杂环如噻吩、呋喃、苯并噻吩或苯并呋喃取代。在所测试的30种衍生物中，鉴定出了两种Ki在纳摩尔范围内的衍生物10和39（分别为2.3和3 nM）。它们对α4β2烟碱受体表现出严格的选择性（高达1 μM），但与5HT3受体相互作用，Ki约为3 nM。报告了衍生物的合成、构效关系研究及完整描述。
